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Inhibition of GRK2 mitigates renal fibrosis via oxidative stress pathway

Jiangrui Cheng1, Xiao Jiang2, Qinxiang Deng1

  • 1Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Centre of Anti-Inflammatory and Immune Medicine, Center of Rheumatoid Arthritis of Anhui Medical University, Hefei, 230032, China.

European Journal of Pharmacology
|July 2, 2025
PubMed
Abstract

Insights

Pharmacological inhibition of G protein-coupled receptor kinase 2 (GRK2) alleviates renal fibrosis. Blocking GRK2 reduces oxidative stress and inflammation, offering a potential therapeutic target for kidney disease.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Pharmacology

Background:

  • G protein-coupled receptor kinase 2 (GRK2) plays a role in various diseases.
  • GRK2 functional changes are implicated in disease pathogenesis.
  • The specific role of GRK2 in renal fibrosis requires further investigation.

Purpose of the Study:

  • To investigate the role of GRK2 in renal fibrosis.
  • To evaluate the protective effects of GRK2 inhibition in renal fibrosis models.
  • To explore the therapeutic potential of targeting GRK2 for renal fibrosis treatment.

Main Methods:

  • Established unilateral ureteral occlusion (UUO) and ischemia-reperfusion (I/R) mouse models.
  • Utilized GRK2 knockdown (GRK2-KD), GRK2 conditional-knockdown (GRK2-CKd), and wild-type (WT) mice.
  • Conducted in vitro studies using GRK2 knockout (GRK2-KO) cells and assessed pharmacological GRK2 inhibition.

Main Results:

  • UUO/I/R models showed increased GRK2 and NADPH oxidase 4 (NOX4) expression and pathological damage.
  • GRK2 knockdown ameliorated renal function, reduced NOX4 and oxidative stress.
  • In vitro, GRK2 knockout reduced NOX4, oxidative stress, and modulated epithelial-mesenchymal transition (EMT) markers. Pharmacological inhibition with CP-25 or paroxetine improved fibrosis.

Conclusions:

  • Pharmacological GRK2 blockade with CP-25 or paroxetine effectively reduces renal fibrosis.
  • GRK2 inhibition alleviates fibrosis by regulating NOX4 and oxidative stress.
  • GRK2 is a promising therapeutic target for renal fibrosis and inflammation.
Keywords:
Chronic kidney diseaseEpithelial-mesenchymal transitionGRK2NOX4Renal fibrosis

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